Overadjustment Bias as a Threat in the Drive for Gender Equity

No abstract available

https://ift.tt/2ubWHvr

The Safety and Efficacy of Laparoscopic Common Bile Duct Exploration Combined with Cholecystectomy for the Management of Cholecysto-choledocholithiasis: An Up-to-date Meta-analysis

Objective: The aim of this study was to compare the efficacy and safety of the laparoscopic common bile duct exploration (LCBDE) and laparoscopic cholecystectomy (LC) with preoperative endoscopic sphincterotomy (pre-EST) and LC for concomitant gallstones and common bile duct (CBD) stones. Background: It remains controversial whether LCBDE+LC is better than pre-EST+LC for gallstones and CBD stones. Methods: A specific search of online databases was performed from January 2006 to October 2017. Relative outcomes of perioperative safety and postoperative efficacy were synthesized. Single-arm meta-analysis and cumulative meta-analysis were also conducted. Results: A total of 13 studies involving 1757 (872 vs 885) patients were included for analysis in our study. The CBD stones clearance rate [94.1% vs 90.1%; odds ratio (OR) 1.56, P = 0.012] was significantly higher in patients who underwent LCBDE+LC than pre-EST+LC, while perioperative complications (7.6% vs 12.0%; OR 0.67, P = 0.015), conversion to other procedure (4.1% vs 7.1%; OR 0.64, P = 0.025), retained stones rate (1.2% vs 7.9%; OR 0.34, P = 0.004), lithiasis recurrence rate (1.8% vs 5.6%, OR 0.32, P = 0.005), operative time [112.28 vs 132.03 minutes; weighted mean difference (WMD) −18.08, P = 0.002], length of hospital stay (4.94 vs 6.62 days; WMD −1.63, P = 0.023), and total charges [standardized mean difference (SMD) −2.76, P = 0.002] were significantly lower in LCBDE+LC. The mortality (0.6% vs 1.1%; OR 0.32, P = 0.117) was similar between the 2 groups. The cumulative meta-analyses indicated the effect sizes of CBD stones clearance rate, perioperative complications, and conversion to other procedure have already stabilized between 2 groups. Conclusion: The updated meta-analysis first confirms that LCBDE+LC is superior to pre-EST+LC both in perioperative safety and short- and long-term postoperative efficacy, which should be considered as optimal treatment choice for cholecysto-choledocholithiasis.

https://ift.tt/2umGqDj

Mendelian Randomization: Progressing towards understanding causality

Annals of Neurology, Volume 0, Issue ja, -Not available-.


https://ift.tt/2mo3y0N

Mendelian randomization study shows no causal relationship between circulating urate levels and Parkinson's disease

Annals of Neurology, Volume 0, Issue ja, -Not available-.


https://ift.tt/2zHni8Q

Plasma urate and risk of Parkinson's disease: a Mendelian randomization study

Annals of Neurology, Volume 0, Issue ja, -Not available-.


https://ift.tt/2mmBZEY

Notch3ECD immunotherapy improves cerebrovascular responses in CADASIL mice

Annals of Neurology, Volume 0, Issue ja, -Not available-.


https://ift.tt/2zGR8ul

Identifying therapeutic targets from spontaneous beneficial brain lesions

Annals of Neurology, Volume 0, Issue ja, -Not available-.


https://ift.tt/2mk453E

The clinical significance of PINX1 expression in papillary thyroid carcinoma

PIN2/TERF1 interacting telomerase inhibitor 1 (PINX1) is a telomerase inhibitor located on human chromosome 8p23, and also act as a tumor suppressor in several types of cancers, including breast, gastric, ovarian and bladder cancer; However, the role of PINX1 expression in papillary thyroid carcinoma (PTC) has not been defined. Therefore, we investigated the role of PINX1 expression in PTC by analyzing the correlation between PINX1 expression and various clinicopathological factors. Immunohistochemistry for PINX1 was performed using a tissue microarray of samples taken from the 160 patients with PTC.

https://ift.tt/2zMDXbo

Prevalence of and Risk Factors for Colorectal Neoplasia in Asymptomatic Young Adults (20–39 Years Old)

The incidence of colorectal cancer is increasing among persons 50 years old or younger. However, data on the epidemiology of young-onset colorectal neoplasia (CRN) are limited. Although some studies have investigated the epidemiology of CRN in persons younger than 50 years, most have focused on persons 40 years or older. We evaluated the prevalence of and risk factors for CRN in adults younger than 40 years.

https://ift.tt/2uvGsJS

Cryotherapy relieves pain and edema following inguinal hernioplasty in males with end-stage renal disease: A prospective randomized study

Tension free hernioplasty under local anesthetic infiltration is a reasonable choice for end-stage renal disease patients with hernia.

https://ift.tt/2L1UL3n

Quality of communication and trust in patients with serious illness: An exploratory study of the relationships of race/ethnicity, socioeconomic status and religiosity

Better understanding of clinicians' skill communicating with their patients, and of patients' trust in clinicians, is necessary to develop culturally-sensitive palliative care interventions. Race/ethnicity, socioeconomic status, and religiosity have been documented as factors influencing quality of communication and trust.

https://ift.tt/2Nl80Zq

Terminally Ill Cancer Patients’ Concordance between Preferred Life-Sustaining Treatment States in Their Last 6 Months of Life and Received Life-Sustaining Treatment States in Their Last Month: An Observational Study

The extent to which patients' preferences for end-of-life (EOL) care are honored may be distorted if preferences are measured long before death, a common approach of existing research. We examined the concordance between cancer patients' states of life-sustaining treatments (LSTs) received in their last month and LST-preference states assessed longitudinally over their last 6 months.

https://ift.tt/2L5pexy

Cultural factors influencing Advance Care Planning in progressive, incurable disease: A systematic review with narrative synthesis

Advance care planning (ACP) can improve end-of-life outcomes, but low uptake indicates it is less acceptable to patients of some cultural backgrounds.

https://ift.tt/2Js8N8M

Taste alterations during treatment with protein kinase inhibitors: a pilot study

Protein kinase inhibitors (PKIs) have caused a major survival improvement for patients with certain advanced cancers, like renal cell carcinoma and lung cancer. Due to increased clinical use of these agents, physicians are faced with a new spectrum of toxicities.(1) One of the most common toxicities is patient-reported taste alterations, which may impair nutritional intake and quality of life.(1-3)

https://ift.tt/2L3f544

Advance care planning with patients who have end-stage kidney disease: a systematic realist review

Patients with end-stage kidney disease have a high mortality rate and disease burden. Despite this, many do not speak with healthcare professionals about end-of-life issues. Advance care planning is recommended in this context but is complex and challenging. We carried out a realist review to identify factors affecting its implementation.

https://ift.tt/2JuBi5C

Evaluation of N-Succinimidyl S-Acetylthioacetate Ligand for Radiolabeling of Humanized Antibodies with 188Rhenium

Cancer Biotherapy and Radiopharmaceuticals, Ahead of Print.


https://ift.tt/2Jt9y1l

Point-of-care umbilical arterial lactate and newborn outcomes in a low resource setting: cohort study

Birth asphyxia contributes substantially to the burden of intrapartum stillbirth and neonatal mortality in resource limited countries. We investigated clinical correlates and neonatal outcomes of lactate analy...

https://ift.tt/2uzBo6y

Consistency of Integrated Management of Newborn and Childhood Illness (IMNCI) in Shire Governmental Health Institution in 2017

In an effort to reduce infant mortality and morbidity, the World Health Organization and other technical partners developed the Integrated Management of Newborn and Childhood Illness (IMNCI). This study focuse...

https://ift.tt/2LapzOH

Cranial neural tube defect after trimethoprim exposure

The Neural Tube Defects Research Group of University of Malaya was approached to analyze a tablet named TELSE, which may have resulted in a baby born with central nervous system malformation at the University ...

https://ift.tt/2LqbU2S

Knowledge is power: general practitioners prescribing of new oral anticoagulants in Ireland

New oral anticoagulants (NOACs) aim to overcome warfarin's shortcomings, however their pharmacokinetic characteristics make prescribing complex. Thus it is imperative that general practitioners (GPs) are aware...

https://ift.tt/2LhfEXi

Imprint cytology: a useful screening test for diagnosis of Helicobacter pylori in resource poor settings

The study aimed to compare the usefulness of two staining methods for imprint cytology for diagnosis of Helicobacter pylori infection. Gastric biopsy specimens (from dyspeptic patients attending routine upper gas...

https://ift.tt/2LqbJoe

Maternal Proteins That Are Phosphoregulated upon Egg Activation Include Crucial Factors for Oogenesis, Egg Activation and Embryogenesis in Drosophila melanogaster

Egg activation is essential for the successful transition from a mature oocyte to a developmentally competent egg. It consists of a series of events including the resumption and completion of meiosis, initiation of translation of some maternal mRNAs and destruction of others, and changes to the vitelline envelope. This major change of cell state is accompanied by large scale alteration in the oocyte's phosphoproteome. We hypothesize that the cohort of proteins that are subject to phosphoregulation during egg activation are functionally important for processes before, during, or soon after this transition, potentially uniquely or as proteins carrying out essential cellular functions like those they do in other (somatic) cells. In this study, we used germline-specific RNAi to examine the function of 189 maternal proteins that are phosphoregulated during egg activation in Drosophila melanogaster. We identified 53 genes whose knockdown reduced or abolished egg production and caused a range of defects in ovarian morphology, as well as 51 genes whose knockdown led to significant impairment or abolishment of the egg hatchability. We observed different stages of developmental arrest in the embryos and various defects in spindle morphology and aberrant centrosome activities in the early arrested embryos. Our results, validated by the detection of multiple genes with previously-documented maternal effect phenotypes among the proteins we tested, revealed 15 genes with newly discovered roles in egg activation and early embryogenesis in Drosophila. Given that protein phosphoregulation is a conserved characteristic of this developmental transition, we suggest that the phosphoregulated proteins may provide a rich pool of candidates for the identification of important players in the egg-to-embryo transition.

https://ift.tt/2moddnK

Overexpression of eis without a mutation in promoter region of amikacin- and kanamycin-resistant Mycobacterium tuberculosis clinical strain

Aminoglycosides such as amikacin and kanamycin are effective injectable second-line drugs for treatment of multidrug-resistant tuberculosis. Molecular mechanisms underlying aminoglycoside resistance are not we...

https://ift.tt/2mos6Xy

The Dengue virus in Nepal: gaps in diagnosis and surveillance

The introduction of the dengue virus (DENV) in Nepal is recent, first reports date back to 2004 from a Japanese traveller and limited information is available about DENV infection in the Nepali population. Wit...

https://ift.tt/2mnzmTv

IFNL4-{Delta}G allele is associated with an interferon signature in tumors and survival of African-American men with prostate cancer

Purpose: Men of African ancestry experience an excessive prostate cancer mortality that could be related to an aggressive tumor biology. We previously described an immune-inflammation signature in prostate tumors of African-American patients. Here, we further deconstructed this signature and investigated its relationships with tumor biology, survival, and a common germline variant in the interferon 4 (IFNL4) gene. Experimental Design: We analyzed gene expression in prostate tissue datasets and performed genotype and survival analyses. We also overexpressed IFNL4 in human prostate cancer cells. Results: We found that a distinct interferon signature that is analogous to the previously described "Interferon-related DNA Damage Resistance Signature" (IRDS) occurs in prostate tumors. Evaluation of two independent patient cohorts revealed that IRDS is detected about twice as often in prostate tumors of African-American than European-American men. Furthermore, analysis in The Cancer Genome Atlas (TCGA) showed an association of increased IRDS in prostate tumors with decreased disease-free survival. To explain these observations, we assessed whether IRDS is associated with an IFNL4 germline variant (rs368234815-G) that controls production of IFN-4 a type-III interferon, and is most common in individuals of African ancestry. We show that the IFNL4 rs368234815-G allele was significantly associated with IRDS in prostate tumors and overall survival of African-American patients. Moreover, IFNL4 overexpression induced IRDS in three human prostate cancer cell lines. Conclusions: Our study links a germline variant that controls production of IFN-4 to the occurrence of a clinically relevant interferon signature in prostate tumors that may predominantly affect men of African ancestry.

https://ift.tt/2urPlEi

Metformin Inhibits Prostate Cancer Progression by Targeting Tumor-Associated Inflammatory Infiltration

Purpose: Inflammatory infiltration plays important roles in both carcinogenesis and metastasis. We are interested in understanding the inhibitory mechanism of metformin on tumor-associated inflammation in prostate cancer. Experimental Design: By using TRAMP mouse model, in vitro macrophage migration assays, and patient samples, we examined the effect of metformin on tumor-associated inflammation during the initiation and after androgen deprivation therapy of prostate cancer. Results: Treating TRAMP mice with metformin delays prostate cancer progression from LGPIN to HGPIN, WD to UD, and PIN to adenocarcinoma with concurrent inhibition of inflammatory infiltration evidenced by reduced recruitment of macrophages. Furthermore, metformin is capable of inhibiting the following processes: inflammatory infiltration after ADT induced by surgically castration in mice, bicalutamide treatment in patients and hormone deprivation in LNCaP cells. Mechanistically, metformin represses inflammatory infiltration by downregulating both COX2 and PGE2 in tumor cells. Conclusions: Metformin is capable of repressing prostate cancer progression by inhibiting infiltration of tumor-associated macrophages, especially those induced by ADT, by inhibiting COX2/PGE2 axis, suggesting that a combination of ADT with metformin could be a more efficient therapeutic strategy for prostate cancer treatment.

https://ift.tt/2zLyGRd

Evolutionary expression of HER2 conferred by chromosome aneuploidy on circulating gastric cancer cells contributes to developing targeted and chemotherapeutic resistance

Purpose: Previous human epidermal growth factor receptor-2 (HER2)-derived resistance studies were based on ex vivo models, which could not mirror evolutionary expression of HER2 during therapy. To investigate dynamic expression of HER2 and its contribution to developing therapeutic resistance conferred by chromosome aneuploidy, both HER2 phenotype and chromosome 8 aneuploidy on CTCs were co-examined in advanced gastric cancer (AGC) patients. Experimental Design: Total of 115 AGC patients, including 56 of histo-pathological HER2⁺ (hHER2⁺) subjects who received first-line HER2-targeted therapy plus chemotherapy, and 59 of hHER2^- patients who received chemotherapy alone, were prospectively enrolled. Both HER2 phenotype and Chr8 aneuploidy of CTCs in patients were co-examined by HER2-iFISH during therapy. Results: A fluctuated positive HER2 phenotype on CTCs (cHER2⁺) was revealed, showing cHER2⁺ at different time intervals during treatment. Acquisition of cHER2⁺ phenotype in 91.0% of hHER2⁺ and 76.2% hHER2^- patients was demonstrated to correlate with development of resistance to trastuzumab-targeted therapy for hHER2⁺ patientsand chemotherapy alone for hHER2^- patients. Aneuploid Chr8 was demonstrated to participate in acquisition of cHER2⁺ phenotype, which provides a growth advantage to HER2⁺ CTCs against therapeutic pressure, leading to development of therapeutic resistance. Conclusions: Comparing to low positivity of conventional histo-pathological hHER2 examination routinely performed once, significant higher positivity of cHER2⁺ on CTCs was observed. Continuously examining cHER2 possesses unique advantages with respect to monitoring therapeutic resistance in real time in carcinoma patients. Moreover, contribution of chromosome aneuploidy to phenotypic evolution of HER2 expression on CTCs may help elucidate underlying mechanisms of developing therapeutic resistance.

https://ift.tt/2urG6Uv

Phase 1 Study of Seviteronel, a Selective CYP17 Lyase and Androgen Receptor Inhibitor, in Men with Castration-Resistant Prostate Cancer

Purpose: Seviteronel (INO-464) is a selective cytochrome P450c17a (CYP17) 17,20-lyase (lyase) and androgen receptor (AR) inhibitor with anti-tumor activity in vitro and in vivo. This open-label phase 1 clinical study evaluated the safety, tolerability, pharmacokinetics (PK) and activity of once daily (QD) seviteronel in male chemotherapy-naïve subjects with castrate-resistant prostate cancer (CRPC). Experimental Design: Seviteronel was administered at 600 mg QD with dose titration (DT) and in modified 3+3 dose escalation QD cohorts at 600 mg, 750 mg, and 900 mg without DT. The primary objectives of this study were to establish safety, tolerability and the maximum tolerated dose of seviteronel in chemotherapy-naïve subjects with or without prior treatment with FDA-approved CRPC treatments, abiraterone acetate (AA) and enzalutamide (ENZA). Secondary objectives were to assess PK, PSA, tumor response and endocrine results. Results: Twenty-one subjects were enrolled. No dose-limiting toxicities (DLTs) were observed through 750 mg QD. Most treatment-emergent adverse events (AEs) reported at grade1-2. The most commonly reported AEs were fatigue (71%), dizziness (52%), vision blurred (38%) and dysgeusia (33%), with most AEs improving after dose reduction or dose interruption. Conclusions: Once-daily seviteronel was generally well tolerated in this phase 1 study of men with CRPC, a majority of which had progressed on prior AA or ENZA, or both. Of the doses evaluated, 600 mg QD was chosen as the recommended phase 2 dose for future studies in subjects with CRPC.

https://ift.tt/2LnteW8

The splicing factor PTBP1 promotes expression of oncogenic splice variants and predicts poor prognosis in patients with non-muscle invasive bladder cancer.

Purpose: Non-muscle invasive bladder cancer (NMIBC) is a malignant disease characterized by high heterogeneity, which corresponds to dysregulated gene expression and alternative splicing (AS) profiles. Bioinformatics analyses of splicing factors potentially linked to bladder cancer progression identified the heterogeneous nuclear ribonucleoprotein I (i.e. PTBP1) as candidate. This study aimed at investigating whether PTBP1 expression associates with clinical outcome in NMIBC patients. Experimental Design: A cohort of 152 patients presenting primary NMIBC (pTa-pT1) was enrolled. Primary NMIBCs were assessed for PTBP1 expression by immunohistochemistry (IHC) and the results were correlated with clinical data using Kaplan-Meier curves and Cox regression analyses. Cell proliferation and survival assays were performed to assess the function of PTBP1. Furthermore, the impact of PTBP1 on the AS pattern of specific bladder cancer-related genes was investigated in cancer cell lines and in patient's specimens. Results: Public datasets querying highlighted a positive correlation between PTBP1 expression and NMIBC progression, which was then confirmed by IHC analysis. High PTBP1 expression was associated with worse clinical outcome in terms of incidence of tumor relapse and survival in NMIBC patients. Interestingly, down-regulation of PTBP1 in bladder cancer cell lines affected pro-survival features. Accordingly, PTBP1 modulated AS of bladder cancer-related genes in cell lines and patient's specimens. Conclusion(s): PTBP1 expression correlates with disease progression, poor prognosis and worse survival in NMIBC patients. Down-regulation of PTBP1 expression affects pro-survival features of bladder cancer cells and modulates AS of genes with relevance for bladder cancer, suggesting its role as outcome-predictor in this disease.

https://ift.tt/2uu9F7X

Activating transcription factor 4 modulates TGF{beta}-induced aggressiveness in triple negative breast cancer via SMAD2/3/4 and mTORC2 signaling

Purpose: Based on the identified stress-independent cellular functions of activating transcription factor 4 (ATF4), we reported enhanced ATF4 levels in MCF10A cells treated with TGFβ1. ATF4 is overexpressed in triple negative breast cancer (TNBC) patients, but its impact on patient survival and the underlying mechanisms remain unknown. We aimed to determine ATF4 effects on breast cancer patient survival and TNBC aggressiveness, and the relationships between TGFβ and ATF4. Defining the signaling pathways may help us identify a cell signaling-tailored gene signature. Experimental Design: Patient survival data was determined by Kaplan-Meier analysis. Relationship between TGFβ and ATF4, their effects on aggressiveness (tumor proliferation, metastasis, and stemness), and the underlying pathways were analyzed in three TNBC cell lines and in vivo using patient-derived xenografts (PDXs). Results: ATF4 overexpression correlated with TNBC patient survival decrease and a SMAD-dependent crosstalk between ATF4 and TGFβ was identified. ATF4 expression inhibition reduced migration, invasiveness, mammosphere-forming efficiency, proliferation, epithelial-mesenchymal transition, and antiapoptotic and stemness marker levels. In PDX models, ATF4 silencing decreased metastases, tumor growth, and relapse after chemotherapy. ATF4 was shown to be active downstream of SMAD2/3/4 and mTORC2, regulating TGFβ/SMAD and mTOR/RAC1-RHOA pathways independently of stress. We defined an eight-gene signature with prognostic potential, altered in 45% of 2509 breast cancer patients. Conclusions: ATF4 may represent a valuable prognostic biomarker and therapeutic target in TNBC patients, and we identified a cell-signaling pathway-based gene signature that may contribute to the development of combinatorial targeted therapies for breast cancer.

https://ift.tt/2zGV3qQ

Deficits in mesolimbic reward pathway underlie social interaction impairments in children with autism

Abstract

Lack of interest in social interaction is a hallmark of autism spectrum disorder. Animal studies have implicated the mesolimbic reward pathway in driving and reinforcing social behaviour, but little is known about the integrity of this pathway and its behavioural consequences in children with autism spectrum disorder. Here we test the hypothesis that the structural and functional integrity of the mesolimbic reward pathway is aberrant in children with autism spectrum disorder, and these aberrancies contribute to the social interaction impairments. We examine structural and functional connectivity of the mesolimbic reward pathway in two independent cohorts totalling 82 children aged 7–13 years with autism spectrum disorder and age-, gender-, and intelligence quotient-matched typically developing children (primary cohort: children with autism spectrum disorder n = 24, typically developing children n = 24; replication cohort: children with autism spectrum disorder n = 17, typically developing children n = 17), using high angular resolution diffusion-weighted imaging and functional MRI data. We reliably identify white matter tracts linking—the nucleus accumbens and the ventral tegmental area—key subcortical nodes of the mesolimbic reward pathway, and provide reproducible evidence for structural aberrations in these tracts in children with autism spectrum disorder. Further, we show that structural aberrations are accompanied by aberrant functional interactions between nucleus accumbens and ventral tegmental area in response to social stimuli. Crucially, we demonstrate that both structural and functional circuit aberrations in the mesolimbic reward pathway are related to parent-report measures of social interaction impairments in affected children. Our findings, replicated across two independent cohorts, reveal that deficits in the mesolimbic reward pathway contribute to impaired social skills in childhood autism, and provide fundamental insights into neurobiological mechanisms underlying reduced social interest in humans.

https://ift.tt/2LeAKWs

Effective diagnosis of persistent facial pain will benefit patients and save money

Patients with persistent facial pain are costing the economy more than £3,000 each per year, new research has revealed.

https://ift.tt/2LmTSOG

CD38-mediated immunosuppression as a mechanism of tumor cell escape from PD-1/PD-L1 blockade [Research Articles]

Although treatment with immune checkpoint inhibitors provides promising benefit for cancer patients, optimal use is encumbered by high resistance rates and requires a thorough understanding of resistance mechanisms. We observed that tumors treated with PD-1/PD-L1 blocking antibodies develop resistance through the up-regulation of CD38, which is induced by all-trans retinoic acid (ATRA) and IFN-β in the tumor microenvironment. In vitro and in vivo studies demonstrate that CD38 inhibits CD8+ T cell function via adenosine receptor signaling, and that CD38 or adenosine receptor blockade are effective strategies to overcome the resistance. Large datasets of human tumors reveal expression of CD38 in a subset of tumors with high levels of basal or treatment-induced T cell infiltration, where immune checkpoint therapies are thought to be most effective. These findings provide a novel mechanism of acquired resistance to immune checkpoint therapy and an opportunity to expand their efficacy in cancer treatment.

https://ift.tt/2LndZwt

CARs versus BiTEs: A Comparison between T Cell-Redirection Strategies for Cancer Treatment [Reviews]

The redirection of T cells against tumors holds much promise for the treatment of cancer. Two main approaches for T-cell redirection involve their genetic modification with chimeric antigen receptors (CAR), or the use of recombinant proteins designated bispecific T-cell engagers (BiTE). These approaches have demonstrated dramatic effects in patients with hematologic cancers, although limited effect against solid cancers. Here, we review and compare the successes and challenges of these two types of immunotherapies, with special focus on their mechanisms, and discuss strategies to improve their efficacy against cancer.

Significance: CAR and BiTE cancer therapies have generated much excitement, but although the therapies are potentially competitive, information directly comparing the two is difficult to obtain. Here, we present the fundamentals of each approach and compare the range and level of functions they can elicit from T cells, and their efficacy against cancers. Cancer Discov; 8(8); 1–11. ©2018 AACR.

https://ift.tt/2Li3AVQ

Microdialysis Study of Aztreonam-Avibactam Distribution in Peritoneal Fluid and Muscle of Rats with or without Experimental Peritonitis [PublishAheadOfPrint]

The purpose of this study was to investigate aztreonam (ATM) and avibactam (AVI) distribution in intraperitoneal fluid and muscle interstitial fluid by microdialysis in rats, with or without peritonitis, and to compare the unbound concentrations in tissue with the unbound concentrations in blood. Microdialysis probes were inserted into the jugular vein, hind leg muscle and peritoneal cavity of control rats (n = 5) and rats with intra-abdominal sepsis (n = 9) induced by cecal ligation and punctures. ATM and AVI probe recoveries in each media were determined for both molecules in each rat by retrodialysis by drug. ATM-AVI combination was administered as an intravenous (IV) bolus at a dose of 100-25 mg⋅kg^-1. Microdialysis samples were collected over 120 min, and ATM-AVI concentrations were determined by LC-MS/MS. Non-compartmental pharmacokinetic analysis was conducted and non-parametric test were used for statistical comparisons between groups (infected versus control) and medium. ATM and AVI distribution in intraperitoneal fluid and muscle was rapid and complete both in control rats and in rats with peritonitis and concentration profiles in blood, intraperitoneal fluid and muscle were virtually superimposed, in control and infected animals, both for ATM and AVI. No statistically significant difference was observed between unbound tissue extracellular fluid (ECF) and systemic areas under the curve for both molecules in control and infected animals. In the present study, intraperitoneal infection induced by cecal ligation and puncture had no apparent effect on ATM and AVI pharmacokinetics in rats.

https://ift.tt/2uAc2W0

Validation of Heelstick Microsampling to Optimize Micafungin Doses in Neonates and Young Infants [PublishAheadOfPrint]

Major gaps exist in our knowledge of antimicrobial pharmacokinetics in critically ill neonates and infants that require validated microsampling and bioanalysis methods to support therapeutic drug monitoring. We compared serially collected intravenous (IV) and heel-stick capillary (HSC) sampled plasma concentrations of micafungin (8 mg/kg) in eight infants born preterm, with systemic candidiasis. The mean (SD) micafungin AUC_inf was 316 (65.0) h·mg/L based on HSC concentrations that strongly correlated (R²= 0.92) with IV values to support dose adjustment.

https://ift.tt/2mlHS5l

Extended Duration MK-8591-Eluting Implant as a Candidate for HIV Treatment and Prevention [PublishAheadOfPrint]

Adherence remains a major hurdle to the success of daily oral drug regimens for the treatment and prevention of HIV infection. Long-acting drug formulations requiring less frequent dosing offer an opportunity to improve adherence and allow for more forgiving options with regard to missed doses. Administration of long-acting formulations in a clinical setting enables healthcare providers to directly track adherence. MK-8591 (4'-ethynyl-2-fluoro-deoxyadenosine; EFdA) is an investigational nucleoside reverse transcriptase translocation inhibitor (NRTTI) drug candidate under investigation as part of a regimen for HIV treatment, with potential utility as a single agent for pre-exposure prophylaxis (PrEP). The active triphosphate of MK-8591 (MK-8591-TP) exhibits protracted intracellular persistence, and together with the potency of MK-8591, supports its consideration for extended duration dosing. Toward this end, drug-eluting implant devices were designed to provide prolonged MK-8591 release in vitro and in vivo. Implants, administered subcutaneously, were studied in rodents and non-human primates to establish MK-8591 pharmacokinetics and intracellular levels of MK-8591-TP. These data were evaluated against pharmacokinetic and pharmacodynamic models as well as data generated in Ph1a and Ph1b clinical studies with once-weekly oral administration of MK-8591. After a single administration in animals, MK-8591 implants achieved clinically relevant drug exposures and sustained drug release, with plasma levels maintained for greater than 6 months that correspond to efficacious MK-8591-TP levels resulting in 1.6 log reduction in viral load. Additional studies of MK-8591 implants for HIV treatment and prevention are warranted.

https://ift.tt/2uGCJZh

Effect of the synthetic bile salt analog CamSA on the hamster model of Clostridium difficile infection [PublishAheadOfPrint]

Clostridium difficile infection (CDI) is the leading cause of antibiotic-associated diarrhea and has gained worldwide notoriety due to emerging hypervirulent strains and high incidence of recurrence. We previously reported protection of mice from CDI using the anti-germinant bile salt analog CamSA. Here we describe the effects of CamSA on the hamster model of CDI. CamSA treatment of hamsters showed no toxicity and did not affect the richness or diversity of gut microbiota; however, minor changes in community composition were observed. Treatment of C. difficile-challenged hamsters with CamSA doubled the mean time to death compared to control hamsters. However, CamSA alone was insufficient to prevent CDI in hamsters. CamSA in conjunction with suboptimal concentrations of vancomycin led to complete protection from CDI in 70% of animals. Protected animals remained disease-free at least 30 days post-challenge and showed no signs of colonic tissue damage. In a delayed treatment model of hamster CDI, CamSA was unable to prevent infection signs and mortality. These data support a putative model where CamSA reduces the number of germinating C. difficile spores but does not prevent all of them from germinating. Vancomycin halts division of any vegetative cells able to outgrow from spores that escape CamSA.

https://ift.tt/2mm8RxC

In vitro antiviral activity of cabotegravir against HIV-2 [PublishAheadOfPrint]

We examined the antiviral activity of the integrase inhibitor (INI) cabotegravir against HIV-2 isolates from INI-naïve individuals. HIV-2 was sensitive to cabotegravir in both single-cycle and spreading infection assays, with EC₅₀ values in the low to sub-nanomolar range; comparable results were obtained for HIV-1 in both assay formats. Our findings suggest that cabotegravir should be evaluated in clinical trials as a potential option for ART and PrEP in HIV-2–prevalent settings.

https://ift.tt/2uGCLjR

Characterization of the AmpC {beta}-lactamase from Burkholderia multivorans [PublishAheadOfPrint]

Burkholderia multivorans is a member of the Burkholderia cepacia complex, a group of >20 related species of nosocomial pathogens that commonly infect individuals suffering from Cystic Fibrosis. β-Lactam antibiotics are recommended as therapy for infections due to B. multivorans, which possesses two β-lactamase genes, bla_penA and bla_AmpC. PenA is a carbapenemase with a substrate profile similar to the Klebsiella pneumoniae carbapenemase (KPC); in addition, expression of PenA is inducible by β-lactams in B. multivorans. Herein, we characterize AmpC from B. multivorans ATCC 17616. AmpC possesses only 38-46% protein identity to non-Burkholderial AmpCs (e.g., PDC-1, CMY-2). Within 49 clinical isolates of B. multivorans, we identified 27 different AmpC variants. Some variants possessed single amino acid substitutions within critical active site motifs (-loop and R2 loop). Purified AmpC1 demonstrated minimal measurable catalytic activity towards β-lactams (i.e., nitrocefin and cephalothin). Moreover, avibactam was a poor inhibitor of AmpC1 (K_{i app} >600 μM) and the acyl-enzyme complex formation with AmpC1 was slow, likely due to lack of productive interactions with active site residues. Interestingly, immunoblotting using a polyclonal anti-AmpC antibody revealed that protein expression of AmpC1 was inducible in B. multivorans ATCC 17616 after growth in sub-inhibitory concentrations of imipenem (1 μg/ml). The AmpC is a unique inducible class C cephalosporinase that may play an ancillary role in B. multivorans compared to PenA, which is the dominant β-lactamase in B. multivorans ATCC 17616.

https://ift.tt/2mm8Ppu

Novel potent capsid assembly modulators regulate multiple steps of the Hepatitis B virus life-cycle [PublishAheadOfPrint]

The assembly of hepatitis B virus (HBV) core proteins (HBc) into capsids represents a critical step of viral replication. HBc has multiple functions during the HBV life cycle, which makes it an attractive target for antiviral therapies. Capsid assembly modulators (CAMs) induce the formation of empty-capsid or aberrant-capsid devoid of pregenomic RNA (pgRNA) and finally block rcDNA neosynthesis and virion progeny. In this study, novel CAMs JNJ-827 and JNJ-890, were found to be potent inhibitors of HBV replication with a respective half maximal effective concentration of 4.7 and 66 nM in HepG2.117 cells. Antiviral profiling in differentiated HepaRG (dHepaRG) cells and primary human hepatocytes (PHH) revealed that these compounds efficiently inhibited HBV replication, as well as de novo establishment of cccDNA. In addition to these two known effects of CAMs, we observed for the first time that a CAM, here JNJ-827, when added post-infection for a short-term period, significantly reduced HBeAg secretion without affecting the levels of cccDNA amount, transcription, and HBsAg secretion. This inhibitory activity resulted from a direct effect of JNJ-827 on HBeAg biogenesis. In a long-term treatment condition using persistently infected dHepaRG cells, JNJ-827 and JNJ-890 reduced HBsAg, concomitantly to a decrease in viral total RNA and pgRNA levels. Altogether, these data demonstrate that some CAMs could interfere with multiple functions of HBc in the viral life cycle.

https://ift.tt/2uGCFJ1

Increased Doses Lead to Higher Drug Exposures of Levofloxacin for the Treatment of Tuberculosis. [PublishAheadOfPrint]

Patients with multidrug-resistant tuberculosis in Peru and South Africa were randomized to weight-banded nominal doses of 11, 14, 17 or 20 mg/kg/day levofloxacin (minimum 750 mg) in combination with other second-line agents. 101 patients were included in noncompartmental pharmacokinetic analyses. Respective median AUC_0-24 were 109.49, 97.86, 145.33 and 207.04 h*mcg/ml. Median Cmax were 11.90, 12.02, 14.86, and 19.17 mcg/ml. Higher levofloxacin doses, up to 1500 mg daily, resulted in higher exposures. ClinicalTrials.gov Identifier: NCT01918397

https://ift.tt/2moRWuo

Evaluation of Oritavancin in Combination with Rifampin, Gentamicin or Linezolid Against Prosthetic Joint Infection-Associated Methicillin-Resistant Staphylococcus aureus Biofilms by Time-Kill Assays [PublishAheadOfPrint]

The anti-biofilm activity of oritavancin in combination with rifampin, gentamicin or linezolid was evaluated against ten prosthetic joint infection (PJI) related methicillin-resistant Staphylococcus aureus (MRSA) by time-kill assays. Oritavancin combined with rifampin demonstrated statistically significant bacterial reductions compared to either antimicrobial alone for all ten isolates (P ≤0.001), with synergy being observed for 80% (8/10) of the isolates. Oritavancin and rifampin combination therapy may be an option for treating MRSA PJI.

https://ift.tt/2zKJWxk

Screening of preselected libraries targeting Mycobacterium abscessus for drug discovery [PublishAheadOfPrint]

Mycobacterium abscessus (Mabs) is intrinsically resistant to many antimycobacterial antibiotics, which presents serious problems in therapy. Here we describe the development of a novel phenotypic-based microscopic and computerized imaging drug screening approach. A pilot screen of 568 compounds from two libraries identified 17 hits. Eleven of these compounds are described for the first time as active against Mabs. The impact of growth media on these compounds' activity was tested revealing that cation-adjusted Mueller Hinton (MHII) broth supports better growth of actively replicating Mabs and improves the associated compounds activity.

https://ift.tt/2mm8KlG

Validation of a dried blood spot ceftriaxone assay in Papua New Guinean children with severe bacterial infections [PublishAheadOfPrint]

Background: Dried blood spot (DBS) antibiotic assays can facilitate pharmacokinetic (PK) studies in situations where venous blood sampling is logistically and/or ethically challenging. In this study we aimed to demonstrate the validity of a DBS ceftriaxone assay in a PK study of children from Papua New Guinea (PNG) with severe illness, a setting in which healthcare resources are limited and anemia is common.

Methods: Using a previously validated liquid chromatography-mass spectroscopy (LC-MS/MS) assay, serial plasma and DBS ceftriaxone concentrations were measured in PNG children aged 5-10 years with acute bacterial meningitis or severe pneumonia. The concentration-time data were incorporated into population PK models.

Results: Ten children were recruited with an admission hematocrit of 0.22-0.52. Raw data demonstrated good correlation between plasma and DBS concentrations (Spearman r_s =0.94 [95% confidence interval 0.91-0.97], P<0.0001). A marked systematic hematocrit bias was observed, with lower hematocrits resulting in underestimation of DBS-predicted plasma concentration. After adjustment for red-cell partitioning and hematocrit bias, a population PK model comparing plasma and DBS-predicted plasma concentrations did not differ in terms of key PK parameters in including clearance, volume of distribution or residual variability.

Conclusion: The performance of the ceftriaxone DBS assay is robust and provides reassurance that this platform can be used as a surrogate for plasma concentrations to provide valid PK and PK/pharmacodynamic studies of severe unwell children hospitalised in a resource limited setting. It highlights the importance of hematocrit bias in validation studies of DBS assays.

https://ift.tt/2uE8nqk

Significantly improved pharmacokinetics enhances in vivo efficacy of APX001 against echinocandin and multidrug resistant Candida isolates in a mouse model of invasive candidiasis [PublishAheadOfPrint]

APX001 is a first-in-class, intravenous and orally available broad-spectrum antifungal agent in clinical development for the treatment of life-threatening invasive fungal infections. The half-life of APX001A, the active moiety of APX001, is significantly shorter in mice than in humans (1.4 – 2.75 h in mice vs 2 – 2.5 days in humans), making exploration of efficacy in mouse models difficult. With pre-treatment of 1-aminobenzotriazole (ABT), a non-specific cytochrome P450 inhibitor, greatly increased plasma exposure of APX001A was observed in different mice strains of both genders. As a consequence, 26 mg/kg APX001 plus ABT sterilized kidneys in mice infected with C. albicans, while APX001 alone at the same dosage only resulted in a modest 0.2 log₁₀ CFU/g burden reduction relative to vehicle control. In the presence of ABT, two days of once daily dosing APX001 at 26 mg/kg also demonstrated significant in vivo efficacy in the treatment of C. glabrata infections in mice. Potent kidney burden reduction was achieved in not only mice infected with either a susceptible strain or echinocandin and multidrug resistant strains. In contrast, the standard of care micafungin was not ineffective in treating infections caused by these resistant C. glabrata isolates.

https://ift.tt/2mnzL8t

Clinical Outcomes of the Oral Suspension versus Delayed-release Tablet Formulations of Posaconazole for Prophylaxis of Invasive Fungal Infections [PublishAheadOfPrint]

Posaconazole is used for prophylaxis for invasive fungal infections (IFIs) among patients with hematologic malignancies. We compared incidence of breakthrough IFI and early discontinuation between patients receiving delayed-release tablet and oral suspension formulations of posaconazole. This was a retrospective cohort study of patients receiving posaconazole between 1/1/2010 and 6/30/2016. We defined probable or proven breakthrough IFI using the European Organization for Research and Treatment of Cancer (EORTC) criteria. Overall, 547 patients received 860 courses of posaconazole (53% oral suspension and 48% tablet); primary indications for prophylaxis were acute myeloid leukemia (69%), graft versus host disease (18%), and myelodysplastic syndrome (3%). There were no significant differences in demographics or indication between patients receiving the different formulations. Incidence and incidence rate of probable or proven IFI were 1.6% or 3.2 per 10,000 posaconazole days. There was no significant difference in the rate of IFI between suspension courses (2.8 per 10,000 posaconazole days) and tablet courses (3.7 per 10,000 posaconazole days) (rate ratio: 0.8, 95% CI: 0.3 to 2.3). Of the 14 proven or probable cases of IFI, 8/14 had posaconazole serum concentrations measured and 7/8 were above 0.7 mcg/mL. Posaconazole was discontinued early in 15.5% of courses; however the frequency of discontinuation was also not significantly different between the tablet (16.5%) and oral suspension (14.6%) formulations (95% CI for difference: -0.13 to 0.06). In conclusion, incidence of breakthrough IFI was low among patients receiving posaconazole prophylaxis, and not significantly different between patients receiving the tablet versus oral suspension formulations.

https://ift.tt/2uGCxcv

Broad spectrum and safety of oral treatment with a promising nitrosylated chalcone in murine leishmaniasis [PublishAheadOfPrint]

The oral efficacy and safety of a leishmanicidal nitro-chalcone (CH8) were studied in BALB/c mouse infections with Leishmania amazonensis and L. infantum. Although ten-fold higher doses of CH8 were needed to produce the same antiparasitic effect as the reference drug miltefosine, the later was nephrotoxic, while CH8 restored disease toxicity markers to normal. This study shows the therapeutic potential of an orally active and hepato/nephroprotective chalcone against both cutaneous and visceral leishmaniasis.

https://ift.tt/2mo51UC

In silico typing and comparative genomic analysis of IncFIIK plasmids: insights into the evolution of replicons, plasmid backbones and resistance determinant profiles [PublishAheadOfPrint]

IncFII_K plasmids are associated with the acquisition and dissemination of multiple antimicrobial resistance in Klebsiella pneumoniae and often encountered in clinical isolates of this species. Since the phylogeny and evolution of IncFII_K plasmids remain unclear, herein we performed large-scale in silico typing and comparative analysis of these plasmids in publicly available bacterial/plasmid genomes. IncFII_K plasmids are prevalent in K. pneumoniae, as found in 69% sequenced genomes, covering 66% sequenced STs (sequence types), but sparse in other Enterobacteriaceae. IncFII_K replicons have three lineages. One IncFII_K allele could be found in distinct K. pneumoniae STs, highlighting the lateral genetic flow of IncFII_K plasmids. A set of 77 IncFII_K plasmids with full sequences were further analysed. A pool of 327 antibiotic resistance genes or remnants were annotated in 75.3% of these plasmids. Plasmid genome comparison reiterated that they often contain other replicons belonging to IncFIA, IncFIB, IncFII_Yp, IncFII_pCRY, IncR, IncL and IncN groups and that they share a conserved backbone featuring an F-like conjugation module that has divergent components responsible for regulation and mating pair stabilization. Further epidemiological studies of IncFII_K plasmids are required due to sample bias of K. pneumoniae genomes in public database. This study provides insights into the evolution and structures of IncFII_K plasmids.

https://ift.tt/2uCYnNZ

Comprehensive substrate characterization of 22 antituberculosis drugs for multiple solute carrier (SLC) uptake transporters, in vitro [PublishAheadOfPrint]

Substrate potential of antituberculosis drugs on SLC transporters are not well characterized to date, despite a well-established understanding of their drug dispositions and pharmacokinetics. In this study, we investigated comprehensively the substrate potentials of the 22 currently available antituberculosis drugs for solute carrier (SLC) family transporter-mediated uptake, using Xenopus laevis oocytes and stably transfected HEK-293 cells in vitro. The result suggested that, ethambutol, isoniazid, amoxicillin, and prothionamide act as novel substrates for the SLC transporters. In addition, in the presence of representative transporter inhibitors, the uptake of the antituberculosis drugs was markedly decreased compared with the uptake in the absence of inhibitor, suggesting involvement of the corresponding transporters. A cellular-uptake study was performed and the K_m values of ethambutol were found to be 526.1 ± 15.6, 212.0 ± 20.1, 336.8 ± 20.1, and 455.0 ± 28 μM for OCT1, OCT2, OCTN1, and OCTN2, respectively. Similarly, the K_m of prothionamide was 805.8 ± 23.4 μM for OCT1, while the K_m values of isoniazid and amoxicillin for OAT3 were 233.7 ± 14.1 and 161.4 ± 10.6 μM, respectively. The estimated in vivo drug-drug interaction indexes, from in vitro transporter inhibition kinetics, for verapamil, probenecid, and ibuprofen against ethambutol, prothionamide, isoniazid, and amoxicillin were found to be potential for clinical drug interactions. In conclusion, this is the first study that, demonstrated 22 antituberculosis drugs interactions with transporters. This study will be helpful for mechanistic understanding of the disposition, drug-drug interactions and pharmacokinetics of these antituberculosis drugs.

https://ift.tt/2moD6nK

Impact of Antibiotic Treatment on the Burden of Nasal Staphylococcus aureus Among Hospitalized Patients [PublishAheadOfPrint]

We examined the impact of systemic antibiotics on the burden of nasal Staphylococcus aureus in hospitalized patients. Of 1482 patients, 237 (16%) had nasal methicillin-susceptible S. aureus (MSSA) and 92 (6%) had nasal methicillin-resistant S. aureus (MRSA) on admission. Treatment regimens including agents with inhibitory activity against MRSA or MSSA significantly reduced the burden of carriage, whereas regimens lacking anti-MRSA activity, including fluoroquinolones, promoted MRSA overgrowth.

https://ift.tt/2zMdCKy

Impact of an antifungal stewardship programme in a tertiary respiratory medicine setting: A prospective real-world study [PublishAheadOfPrint]

There has been an increase in fungal infections in patients with chronic lung disease over the past decades, which is associated with rapidly increasing costs to healthcare systems.

An antifungal stewardship team was introduced to a tertiary cardiopulmonary hospital, consisting of a medical mycologist and pharmacy support providing weekly stewardship ward rounds, twice monthly multidisciplinary team meetings and a dedicated weekly outpatient clinic. A database was set up to record the activity of the stewardship team.

During the first eighteen months of implementation the antifungal stewardship team had reviewed 178 patients, with 285 recommendations made to inpatients, and 287 outpatient visits. The commonest diagnoses treated were allergic bronchopulmonary aspergillosis and chronic pulmonary aspergillosis. Cystic fibrosis was the largest patient group treated followed by asthma and interstitial lung disease. There was a significant, sustained reduction in monthly antifungal expenditure (p=0.005) by £130,000 per month. There was also a significant reduction in antifungal use measured as Defined Daily Dose/100 bed days (p=0.017). There were no significant changes in expenditure on diagnostic tests. There has been a trend toward more patients having therapeutic levels of voriconazole (p=0.086) and a significant increase in therapeutic levels of posaconazole (p<0.0001).

This study shows that an effective antifungal stewardship programme can significantly reduce expenditure in a specialist respiratory service.

https://ift.tt/2modgjH

Effective treatment of the Mycobacterium avium subsp hominissuis and Mycobacterium abscessus sp. infections in macrophages, biofilm and in mice using Liposomal ciprofloxacin [PublishAheadOfPrint]

Non-tuberculosis mycobacteria (NTM) affects an increasing number of individuals worldwide. The infection is more common in patients with chronic lung conditions, and treatment is challenging. Quinolones, such as ciprofloxacin, have been used to treat patients, but the results have not been encouraging. In this report, we evaluate novel formulations of liposome-encapsulated ciprofloxacin (liposomal ciprofloxacin) in vitro and in vivo. Efficacy was examined in macrophages, biofilms and in vivo using intranasal instillation mouse models against Mycobacterium avium and Mycobacterium abscessus. Liposomal ciprofloxacin was significantly more active than free ciprofloxacin in macrophages and biofilms against both pathogens. When evaluated in vivo, the liposomal ciprofloxacin formulations were associated with significant decreases in bacterial loads in the lung of animals infected with M. avium and M. abscessus.

In summary, topical delivery of liposomal ciprofloxacin in the lung at concentrations greater than achieved in the serum can be effective in the treatment of NTM and further evaluation is warranted.

https://ift.tt/2zRfTnQ

In vitro minimal inhibitory concentrations of rifampin and ethambutol, and treatment outcome in Mycobacterium avium complex lung disease [PublishAheadOfPrint]

Although it is known that in vitro minimal inhibitory concentrations (MICs) of rifampin and ethambutol are poorly correlated with clinical response in Mycobacterium avium complex lung disease (MAC-LD), its evidence is limited. This study investigated the association between treatment outcome and in vitro MICs of rifampin and ethambutol in patients with MAC-LD. Among patients diagnosed with macrolide-susceptible MAC-LD between January 2008 and December 2013, 274 patients treated with a standard regimen for ≥12 months until August 2017 and whose in vitro MIC results were available were enrolled at a tertiary referral center in South Korea. The MIC of antimicrobial agents was determined using the broth microdilution method. The mean age of the included patients was 60.4 years. The overall treatment success rate was 79.6% (218/274 patients) and tended to decrease with increasing MICs of rifampin and ethambutol, particularly at MICs ≥8 μg/ml. Treatment success was significantly different between MAC isolates with MIC ≥8 μg/ml for rifampin and ethambutol and those with MIC <8 μg/ml for rifampin and/or ethambutol (64.9% vs. 85.3%, P <0.001). Multivariate analysis showed that a MIC ≥8 μg/ml for both drugs and initial sputum acid-fast bacilli smear positivity were independent factors for unfavorable response (adjusted odds ratio [lsqb]OR[rsqb] 3.154, 95% confidence interval [lsqb]CI[rsqb] 1.641–6.063, P = 0.001; adjusted OR 2.769, 95% CI 1.420–5.399, P = 0.003, respectively). These findings suggested that in vitro MICs of rifampin and ethambutol may be related to treatment outcome in MAC-LD.

https://ift.tt/2mo4Zfs

E-cigarette adverts and childrens perceptions of tobacco smoking harms: an experimental study and meta-analysis

Objectives

Children exposed to electronic cigarette (e-cigarette) adverts may perceive occasional tobacco smoking as less harmful than children not exposed to e-cigarette adverts. Given the potential cross-cueing effects of e-cigarette adverts on tobacco smoking, there is an urgent need to establish whether the effect found in prior research is robust and replicable using a larger sample and a stronger control condition.

Design

A between-subjects experiment with one independent factor of two levels corresponding to the advertisements to which participants were exposed: glamorous adverts for e-cigarettes, or adverts for objects unrelated to smoking or vaping.

Participants

English school children aged 11–16 (n=1449).

Outcomes

Perceived harm of occasional smoking of one or two tobacco cigarettes was the primary outcome. Secondary outcomes included: perceived harm of regular tobacco smoking, susceptibility to tobacco smoking and perceived prevalence of tobacco smoking in young people. Perceptions of using e-cigarettes were gauged by adapting all the outcome measures used to assess perceptions of tobacco smoking.

Results

Tobacco smokers and e-cigarette users were excluded from analyses (final sample n=1057). Children exposed to glamorous e-cigarette adverts perceived the harms of occasional smoking of one or two tobacco cigarettes to be lower than those in the control group (Z=–2.13, p=0.033). An updated meta-analysis comprising three studies with 1935 children confirmed that exposure to different types of e-cigarette adverts (glamorous, healthful, flavoured, non-flavoured) lowers the perceived harm of occasional smoking of one or two tobacco cigarettes (Z=3.21, p=0.001).

Conclusions

This study adds to existing evidence that exposure to e-cigarette adverts reduces children's perceptions of the harm of occasional tobacco smoking.

https://ift.tt/2LlBGF7

Antioxidant extract counteracts the effects of aging on cortical spreading depression and oxidative stress in the brain cortex

Abstract Purpose: To investigate the effects of Murici extract on the brain excitability-dependent phenomenon known as cortical spreading depression (CSD) and on brain oxidative stress. Methods: Adult and aged Wistar rats were supplemented with murici extract (150 mg/kg/day or 300 mg/kg/day) by gavage for fifteen days. Afterwards, the animals were submitted to a CSD electrophysiological recording and to brain oxidative stress evaluation. Results: Our results showed that aging decreased CSD propagation velocity, catalase activity and glutathione/oxidized glutathione ratio (GSH/GSSG) in the brain cortex of the rats, and increased malondialdehyde (MDA) concentrations and superoxide dismutase (SOD) activity. The highest dose (300 mg/kg/day) of murici extract accelerated CSD, whereas the lowest (150mg/kg/day) decelerated, in both adult and aged animals. In contrast, aged animals supplemented with murici extract in both doses presented low MDA levels and high GSG/GSSG ratio in comparison to the control-aged animals. Conclusion: Murici extract supplementation seems to revert detrimental effects in aged brains and could be considered as a strategy in the treatment of pathologies related to aging and cortical spreading depression.

https://ift.tt/2NWqQaG

Effects of hypothermia on lung inflammation in a rat model of meconium aspiration syndrome

Abstract Purpose: To evaluate the effects of hypothermia treatment on meconium-induced inflammation. Methods: Fifteen rats were instilled with human meconium (MEC, 1.5 mL/kg, 65 mg/mL) intratracheally and ventilated for 3 hours. Eight rats that were ventilated and not instilled with meconium served as a sham group. In MEC-hypothermia group, the body temperature was lowered to 33±0.5°C. Analysis of the blood gases, interleukin (IL)-1β, IL-6, IL-8, and tumor necrosis factor (TNF)-α in bronchoalveolar lavage (BAL) fluid samples, and histological analyses of the lungs were performed. Results: The BAL fluid TNF-α, IL-1β, IL-6 and IL-8 concentrations were significantly higher in the MEC-hypothermia group than in the MEC-normothermia (p < 0.001, p < 0.001, p = 0.001, p < 0.001, respectively) and sham-controlled groups (p < 0.001, p < 0.001, p < 0.001, p < 0.001, respectively). Conclusion: Meconium-induced inflammatory cytokine production is affected by the body temperature control.

https://ift.tt/2JtC8iY

Interleukin-4 protects from chemotherapy-induced peripheral neuropathy in mice modal via the stimulation of IL-4/STAT6 signaling

Abstract Purpose: To investigate the possible role of IL-4 signaling pathway in vincristine-induced peripheral neuropathy. Methods: The mouse model of vincristine-induced peripheral neuropathy and interleukin (IL)-4 knockout mice were utilized to investigate the possible role of IL-4 signaling pathway in vincristine-induced peripheral neuropathy. Vincristine induced increased sensitivity to mechanical stimulation was measured by von Frey hair test 7 and 14 days after intraperitoneal administration of 0.1 mg/kg vincristine in mice. Relative expression levels of cytokines were detected by quantitative real-time PCR. STAT6 expression following vincristine treatment was assessed with western blotting. Results: We discovered that IL-4/STAT6 signaling was down-regulated in vincristine-treated mice. Deletion of IL-4 in mice increased the sensitivity to mechanical allodynia. IL-4 knockout mice also produced more pro-inflammatory cytokines, including IL-1β and TNF-α. Notably, co-administration of exogenous recombination IL-4 significantly prevented vincristine-induced mechanical allodynia. Conclusion: Anti-inflammatory cytokine IL-4 protects rodent model from vincristine-induced peripheral neuropathy via the stimulation of IL-4/STAT6 signaling and inhibition of the pro-inflammatory cytokines.

https://ift.tt/2NSz2IJ

The therapeutic effects of curcumin and capsaicin against cyclophosphamide side effects on the uterus in rats

Abstract Purpose: To evaluate the impact of systemic cyclophosphamide treatment on the rat uterus and investigate the potential therapeutic effects of natural antioxidant preparations curcumin and capsaicin against cyclophosphamide side effects. Methods: A 40 healthy adult female Wistar albino rats were used in this study. Rats were randomly divided into four groups to determine the effects of curcumin and capsaicin against Cyclophosphamide side effects on the uterus (n=10 in each group); Group 1 was the control group (sham-operated), Group 2 was the cyclophosphamide group, Group 3 was the cyclophosphamide + curcumin (100mg/kg) group, and Group 4 was the cyclophosphamide + capsaicin (0.5 mg/kg) group. Results: Increased tissue oxidative stress and histological damage in the rat uterus were demonstrated due to the treatment of systemic cyclophosphamide chemotherapy alone. The level of tissue oxidant and antioxidant markers and histopathological changes were improved by the treatment of curcumin and capsaicin. Conclusion: Cytotoxic effects of natural alkylating chemotherapeutic agents like cyclophosphamide on the uterus can be prevented by curcumin and capsaicin.

https://ift.tt/2NnE6nF

An experimental study on the preventive effects of N-acetyl cysteine and ozone treatment against contrast-induced nephropathy

Abstract Purpose: To compare the preventive effects of N-acetyl cysteine (NAC), ozone preconditioning and ozone treatment against contrast-induced nephropathy (CIN) in an experimental rat model. Methods: Thirty adult male Wistar rats were randomly distributed into five groups (n=6 for each group). Group I served as control and Group II had only contrast agent, while Group III received NAC and Group IV received intraperitoneal ozone 6 hours before and 6 hours after introduction of contrast agent. Ozone treatment was applied for 5 days after the contrast agent was introduced in Group V. After induction of CIN, groups were compared in terms of serum levels of urea, creatinine, neutrophil gelatinase associated lipocalin, protein carbonyl, total antioxidant capacity (TAC) as well as degree of renal injury at histopathologic level. Results: Groups II-V displayed more obvious histopathological alterations such as hemorrhage and renal tubular injury compared with Group I. TAC (p=0.043) and creatinine (p=0.046) levels increased significantly in Group II after the intervention. In Group III, protein carbonyl level diminished remarkably (p=0.046), while creatinine level was increased (p=0.046) following the intervention. TAC level was higher in Group IV (p=0.028) and Group V (p=0.026) following the procedure. Conclusion: The N-acetyl cysteine and ozone treatment may alleviate the biochemical and histopathological deleterious effects of contrast-induced nephropathy via enhancement of total antioxidant capacity and decreasing oxidative stress.

https://ift.tt/2NTWN32

Synergistic effect of honey and Nigella sativa on wound healing in rats

Abstract Purpose: To investigate the therapeutic potential of honey, Nigella sativa (N. sativa) and their combination in rat model of excisional wound healing. Methods: A circular excision wound was established in the back region of 50 Wistar rats. Subsequently, they were divided into 5 groups and daily topical administration of lanolin in the control group, honey in the honey group, cold-pressed N. sativa seed oil in the N. sativa groups, mix of 1:1 ratio of honey and N. sativa seed oil in the mix group, and phenytoin cream in the phenytoin group were used. Then, wound surface areas were evaluated using digital camera immediately after the injury and at post excision days 5, 10, 15 and 20. Results: Significant reduction in wound surface area was observed within and between the groups (P < 0.001). In the post excision days 5, 10, 15 and 20 the wound surface areas in the mix group were significantly lower than the other groups followed by the phenytoin, honey, N. sativa, and control groups. Conclusion: The wound healing may be improved and accelerated by using topical solutions of honey, N. sativa seed oil and especially their mixture.

https://ift.tt/2JqFx1X

Cardioprotective effect of lipstatin derivative orlistat on normotensive rats submitted to cardiac ischemia and reperfusion

Abstract Purpose: To evaluate in vivo animal model of cardiac ischemia/reperfusion the cardioprotective activity of pancreatic lipase inhibitor of the orlistat. Methods: Adult male Wistar rats were anesthetized, placed on mechanical ventilation and underwent surgery to induce cardiac I/R by obstructing left descending coronary artery followed by reperfusion to evaluation of ventricular arrhythmias (VA), atrioventricular block (AVB) and lethality (LET) with pancreatic lipase inhibitor orlistat (ORL). At the end of reperfusion, blood samples were collected for determination of triglycerides (TG), very low-density lipoprotein (VLDL), low-density lipoprotein (LDL), high-density lipoprotein (HDL), lactate dehydrogenase (LDH), creatine kinase (CK), and creatine kinase-MB (CK-MB). Results: Treatment with ORL has been able to decrease the incidence of VA, AVB and LET. Besides that, treatment with ORL reduced serum concentrations of CK and LDL, but did not alter the levels of serum concentration of TG, VLDL and HDL. Conclusion: The reduction of ventricular arrhythmias, atrioventricular block, and lethality and serum levels of creatine kinase produced by treatment with orlistat in animal model of cardiac isquemia/reperfusion injury suggest that ORL could be used as an efficient cardioprotective therapeutic strategy to attenuate myocardial damage related to acute myocardial infarction.

https://ift.tt/2NSyToF

A curcumin derivative J147 ameliorates diabetic peripheral neuropathy in streptozotocin (STZ)-induced DPN rat models through negative regulation AMPK on TRPA1

Abstract Purpose: To investigate the specific molecular mechanisms and effects of curcumin derivative J147 on diabetic peripheral neuropathy (DPN). Methods: We constructed streptozotocin (STZ)-induced DPN rat models to detected mechanical withdrawal threshold (MWT) in vivo using Von Frey filaments. In vitro, we measured cell viability and apoptosis, adenosine 5'-monophosphate-activated protein kinase (AMPK) and transient receptor potential A1 (TRPA1) expression using MTT, flow cytometry, qRT-PCR and western blot. Then, TRPA1 expression level and calcium reaction level were assessed in agonist AICAR treated RSC96cells. Results: The results showed that J147reduced MWT in vivo, increased the mRNA and protein level of AMPK, reduced TRPA1 expression and calcium reaction level in AITCR treated RSC96 cells, and had no obvious effect on cell viability and apoptosis. Besides, AMPK negative regulated TRPA1 expression in RSC96 cells. Conclusions: J147 could ameliorate DPN via negative regulation AMPK on TRPA1 in vivo and in vitro. A curcumin derivative J147might be a new therapeutic potential for the treatment of DPN.

https://ift.tt/2Nj4jDO

Impact of 1,25(OH) 2 D 3 on TG content in liver of rats with type 2 diabetes

Abstract Purpose: To evaluate the effects of 1,25 dihydroxy vitamin D3 (1,25(OH)2D3) on the content of triglyceride (TG), as well as on the gene and protein expressions of adiponectin receptor 2 (AdipoR2), p38 mitogen-activated protein kinase (P38MAPK), and lipoprotein lipase (LPL) in the liver of rats with type 2 diabetes mellitus (T2DM) so as to provide theoretical basis for exploring the mechanism by which 1,25(OH)2D3 regulates TG. Methods: Wistar rats were divided into four groups (n=25), with different treatments and detected the gene and protein expressions of AdipoR2, p38MAPK, and LPL in the liver tissue by reverse transcription polymerase chain reaction (RT-PCR) and Western blotting. Meanwhile, the content of TG in the liver tissue was detected by the Enzyme-linked immunosorbent assay. Results: The expression of AdipoR2, p38MAPK, LPL gene and protein in the liver of VitD intervention group was significantly higher than that in T2DM group (P <0.05), while the TG content was significantly lower than that in T2DM group (P <0.05). Conclusion: 1,25(OH)2D3 can decrease the content of TG in the liver, and its mechanism may be achieved by upregulating the expressions of AdipoR2, p38MAPK, and LPL in the liver.

https://ift.tt/2NTWBkk

Development of a model for laparoscopic cholecystectomy video assisted training. A randomized study

Abstract Purpose: To identify the surgical trainee benefits through the use of video assisted training (VAT). Methods: Twelve cases of uncomplicated laparoscopic cholecystectomy (LC) were selected. Edited video segments focused on essential intra-operative anatomical structure identification and critical surgical steps. Evaluation of these videos was constructed on a scoring system based on pre and post-teach tests. Results: The mean value of the pre-teach score was 33.2 ± 18.0 points and in the post-teach test the mean value was 66.7 ± 9.7 points. A statistically significant difference was seen when comparing pre and post-teach results (p<.00001). Conclusion: The widespread and the systematic use of video assisted learning may be a useful and economic tool in adjunct to the surgical training techniques practiced until now throughout the surgical community.

https://ift.tt/2JsJS4Z

Research Progresses in Cancer Stem Cells of Three Common Fertility-Related Female Malignancies

Abstract

With abilities to renew themselves and lead to heterogeneity of tumors, cancer stem cells (CSCs) are similar to stem cells. As three leading causes of death that endanger women's health, breast cancer, ovarian cancer and cervical cancer are characterized by high degree of malignancy, metastasis and recurrence. Associated with women's fertility, these three malignancies are common and representative among females. These years, research findings have suggested that CSCs are closely connected with many cancers (including aforementioned three malignancies) and several processes of tumors such as their genesis and development. CSCs have become great concerns for current cancer treatment and interventions. This paper does not only summarize roles of CSCs in genesis, development, drug resistance, metastasis and recurrence of breast cancer, ovarian cancer and cervical cancer, but also proposes potential methods of treatment and intervention, in hope of inspiring readers and researchers.

https://ift.tt/2JtBbqQ

Occult blood in faeces is associated with all-cause and non-colorectal cancer mortality

Objective

An association between detectable faecal haemoglobin (f-Hb) and both the risk of death from colorectal cancer (CRC) and all-cause mortality has been reported. We set out to confirm or refute this observation in a UK population and to explore the association between f-Hb, as indicated by a positive guaiac faecal occult blood test (gFOBT) result, and different causes of death.

Design

All individuals (134 192) who participated in gFOBT screening in Tayside, Scotland between 29/03/2000 and 29/03/2016 were studied by linking their test result (positive or negative) with mortality data from the National Records of Scotland database and following to 30/03/2016.

Results

Those with a positive test result (n=2714) had a higher risk of dying than those with a negative result, from CRC: HR 7.79 (95% CI 6.13 to 9.89), p<0.0001, (adjusted for, gender, age, deprivation quintile and medication that can cause bleeding) and all non-CRC causes: HR 1.58 (95% CI 1.45 to 1.73), p<0·0001.· In addition, f-Hb detectable by gFOBT was significantly associated with increased risk of dying from circulatory disease, respiratory disease, digestive diseases (excluding CRC), neuropsychological disease, blood and endocrine disease and non-CRC.

Conclusion

The presence of detectable f-Hb is associated with increased risk of death from a wide range of causes.

https://ift.tt/2usE3zM

Occult blood in faeces: a window into health beyond the colorectum?

After decades of research, testing for occult blood in faeces is firmly established as a method to screen for colorectal cancer (CRC). Such testing is based on the relatively simple premise that asymptomatic CRCs, and some CRC precursors, may lose small amounts of blood into faeces. The provocative study by Libby et al in Gut,1 which reports the associations between a positive guaiac faecal occult blood test (gFOBT) result and all-cause as well as non-CRC mortality in the National Health Service Tayside Board area of Scotland, suggests that occult blood in faeces may be telling us more than we might have thought. If the eye is the window to the soul, is a faecal test the window to general health?

The current study confirms and expands on the observations of Chen et al, who reported a gradient relationship between all-cause mortality and faecal haemoglobin (f-Hb) concentration in population-based screening...

https://ift.tt/2zJETwX

Dendriform pulmonary ossification leading to bilateral lung transplant: a case report

Abstract

Metaplastic ossification within the lung is seen in a variety of diseases, usually as sequela of either a separate primary pulmonary parenchymal disease or an underlying cardiac disorder such as valvular disease. Primary intraalveolar ossification or ossification within the alveolar septa is a rare entity. Similarly, it is unusual to see overt, diffuse disease affecting the lung to the point of respiratory failure leading to lung transplant. We present a case of an adult male who underwent bilateral lung transplantation, with the native lung pathology showing diffuse, severe dendriform ossification of the bilateral upper and lower lung lobes. The gross and histologic findings along with the radiographic imaging are reviewed herein. Overall, primary ossification of the lung leading to lung transplant is a rare condition that pulmonologists caring for patients with interstitial lung disease should be aware of as a possible cause of the patient's symptoms and lung dysfunction.

https://ift.tt/2JtczyL

Immunohistochemistry for PAX7 is a useful confirmatory marker for Ewing sarcoma in decalcified bone marrow core biopsy specimens

Abstract

PAX7 has been recently demonstrated to be a highly sensitive marker for Ewing sarcoma, and thus far has only been shown to label a relatively small set of other mesenchymal neoplasms. Because the processing of bone marrow core biopsies can often hinder the performance of immunohistochemical stains, we set out to determine if our laboratory's PAX7 staining protocol effectively detects Ewing sarcoma in Bouin's fixed, decalcified bone marrow core biopsies. We stained ten core biopsies involved by Ewing sarcoma, nine non-involved core biopsies, and 13 core biopsies involved by histologic mimics of Ewing sarcoma. Only the ten biopsies involved by Ewing sarcoma and four biopsies with rhabdomyosarcoma showed strong nuclear PAX7 staining. None of the other tumors demonstrated PAX7 expression. This study demonstrates that the PAX7 staining protocol used in our laboratory is a useful marker for Ewing sarcoma and other PAX7-positive tumors in decalcified bone marrow core biopsies.

https://ift.tt/2L56Dle

Curcumin derivative, 2,6-bis(2-fluorobenzylidene)cyclohexanone (MS65) inhibits interleukin-6 production through suppression of NF-κB and MAPK pathways in histamine-induced human keratinocytes cell (HaCaT)

Histamine is a well-known mediator involved in skin allergic responses through up-regulation of pro-inflammatory cytokines. Antihistamines remain the mainstay of allergy treatment, but they were found limited ...

https://ift.tt/2JtjnMs

Animal-level risk factors associated with foot-and-mouth disease in cattle and buffalo in Egypt

Abstract

There is a paucity of the investigation of risk factors associated with foot-and-mouth disease (FMD) in Egypt. Subsequently, in the present study the impact of risk factors associated with FMD infection was analyzed in cattle and buffalo reared in Qalyubia governorate, Egypt. Serum samples were collected from 288 animals (n = 90 water buffalo (Bubalus bubalis) and n = 198 cattle) and adapted for detection of FMD virus infection by ELISA assay with monoclonal antibody (MELISA) to type serotype O. Direct FMD virus serotype was detected in 115 animals (n = 82 cattle and n = 33 buffalo). Univariate analysis revealed a significant association between FMD infection and the fattening animals (P = 0.024; odds ratio (OR) 2.118; confidence interval (CI) 1.105–4.058). Multivariate statistics demonstrated that locality was the potential risk factors for infection by FMD virus (P = 0.001; OR 31.613; CI 13.791–72.466). The present investigation draws attention and gives the impression to the potential risk factors associated with FMD-infected cases in cattle and buffalo in Qalyubia governorate in Egypt. Recognition of the potential risk factors associated with FMD-infected cases offer a novel approach to construct the best preventive measures.

https://ift.tt/2NkIfsc

Morning Glory Disc Anomaly in a Child with Esotropia

A 12-year-old boy was referred to our ophthalmology clinic to evaluate an ocular deviation on the right eye. His medical and ocular history were unremarkable. Ocular examination revealed a best-corrected visual acuity of 20/200 in the right eye and 20/20 in the left eye, and the right eye was esotropic, at 25 prism diopters according to the Krimsky test. A right relative afferent pupillary defect was noted. Fundus examination of the right eye demonstrated a large optic disc, with a funnel-shaped excavation surrounded by an area of chorioretinal pigment abnormalities.

https://ift.tt/2mpWu3r

A Girl with Delayed Puberty and Bumpy Lips

A 14-year-old girl presented to the endocrine department for evaluation of primary amenorrhea. Her medical history was remarkable for recurrent abdominal pain and diarrhea since infancy, with growth in the third percentile for weight and height. Physical examination revealed "bumpy lips" (Figure 1; available at www.jpeds.com), diastema of her anterior teeth, and several lesions on the tip of the tongue and on the oral mucosa (Figure 2 and Figure 3), suggesting the presence of multiple mucosal/submucosal neuromas.

https://ift.tt/2zGc8Bk

Data Sharing Statements for Clinical Trials: One Step Down the Road

The editorialist discusses Tannenbaum and colleagues' findings, the recently adopted requirement for data sharing statements, and how each relates to efforts to ensure that the scientific community learns all it can from clinical trials.

https://ift.tt/2NSl0H3

Harms Reporting in Randomized Controlled Trials of Interventions Aimed at Modifying Microbiota A Systematic Review

Background:

Probiotics, prebiotics, and synbiotics are used increasingly, although the safety and potential harms of these interventions are poorly understood.

Purpose:

To examine how harms-related information is reported in publications of randomized controlled trials (RCTs) of probiotics, prebiotics, and synbiotics.

Data Sources:

Cochrane Central Register of Controlled Trials, PubMed, EMBASE, and Web of Science (without language restrictions) from 1 January 2015 to 20 March 2018.

Study Selection:

RCTs assessing the safety or efficacy of at least 1 intervention involving probiotics, prebiotics, or synbiotics alone or in combination with another intervention compared with any control (such as a placebo or an antibiotic) for any clinical condition.

Data Extraction:

4 reviewers independently assessed study characteristics, the reporting of harms, and the presentation of safety results.

Data Synthesis:

Of 384 trials conducted in healthy volunteers (n = 136) or patients with any of several medical conditions (n = 248), 339 (88%) were published in specialty journals. Trials most often evaluated probiotics (n = 265 [69%]). Studies in persons with medical conditions enrolled outpatients (n = 195) and high-risk patients (n = 53). No harms-related data were reported for 106 trials (28%), safety results were not reported for 142 (37%), and the number of serious adverse events (SAEs) per study group was not given for 309 (80%). Of 242 studies mentioning harms-related results, 37% (n = 89) used only generic statements to describe AEs and 16% (n = 38) used inadequate metrics. Overall, 375 trials (98%) did not give a definition for AEs or SAEs, the number of participant withdrawals due to harms, or the number of AEs and SAEs per study group with denominators.

Limitation:

Journal publication processes may have affected the completeness of reporting; only English-language publications were examined.

Conclusion:

Harms reporting in published reports of RCTs assessing probiotics, prebiotics, and synbiotics often is lacking or inadequate. We cannot broadly conclude that these interventions are safe without reporting safety data.

Primary Funding Source:

No specific funding.

https://ift.tt/2NkGCuI

Zika in 2018: Advising Travelers Amid Changing Incidence

Since it peak in 2016, the prevalence of Zika virus has decreased; at the same time, travel to Zika-affected countries has rebounded. Many gaps remain in our knowledge about key features of this viral infection, making it difficult to counsel patients who are contemplating travel to Zika-affected countries and to determine appropriate testing strategies on their return. The authors outline what is currently known and unknown about this unprecedented viral infection and suggest an approach to shared decision making between travel medicine providers and patients.

https://ift.tt/2NgvfDS

Early Experiences With Journal Data Sharing Policies: A Survey of Published Clinical Trial Investigators

https://ift.tt/2NSm4L8

Making the Voices of Female Trainees Heard

Female physicians are less likely to become full professors and are paid lower salaries than their male colleagues. This article describes the discovery of a gender disparity in "shout-outs" in a residency program and actions that rectified the disparity.

https://ift.tt/2NmrGwe

Relationships between tumour response and primary tumour location, and predictors of long-term survival, in patients with RAS wild-type metastatic colorectal cancer receiving first-line panitumumab therapy: retrospective analyses of the PRIME and PEAK clinical trials

https://ift.tt/2uB5d6M

Delayed intra-articular pseudoaneurysm of the dorsalis pedis artery following arthroscopic Broström results in an unusual clinical presentation

Abstract

Pseudoaneurysms of the dorsalis pedis artery are rare complications following arthroscopic surgery. This manuscript reports a case of an intra-articular pseudoaneurysm presenting nearly 5 months following an arthroscopic Broström procedure. The rarity of this complication and the patient's unusual clinical presentation prompted the use of imaging to diagnose the problem and guide management. Although imaging artifacts are often a nuisance, recognition of clinically relevant artifacts can help make a diagnosis. This case illustrates such a situation.

https://ift.tt/2NWP7wX

Review: In type 2 diabetes, SGLT-2 inhibitors or GLP-1 agonists reduce mortality vs control or DPP-4 inhibitors

https://ift.tt/2mpKqPH

Review: After PCI in AF, OAC plus single vs dual antiplatelets reduces major bleeding; no difference for MACE

https://ift.tt/2mkX8iN

An Innovative Program to Support Gender Equity and Success in Academic Medicine: Early Experiences From the Doris Duke Charitable Foundation's Fund to Retain Clinical Scientists

https://ift.tt/2G5DeUp

Clinicians' Perspectives on Providing Emergency-Only Hemodialysis to Undocumented Immigrants A Qualitative Study

Background:

In the United States, nearly half of undocumented immigrants with end-stage kidney disease receive hemodialysis only when they are evaluated in an emergency department and are found to have life-threatening renal failure ("emergency-only hemodialysis" [EOHD]). These patients experience psychosocial distress and much higher mortality than patients receiving regularly scheduled hemodialysis, but little is known about how providing EOHD affects the clinicians involved.

Objective:

To understand clinicians' experiences providing EOHD.

Design:

Qualitative study using semistructured interviews.

Setting:

A safety-net hospital in Denver, Colorado, and a safety-net system in Houston, Texas.

Participants:

Fifty interdisciplinary clinicians experienced in providing EOHD.

Measurements:

Interviews were analyzed using thematic analysis. Outcomes included themes and subthemes.

Results:

Four themes and 13 subthemes (in parentheses) were identified: 1) drivers of professional burnout (emotional exhaustion from witnessing needless suffering and high mortality, jeopardizing patient trust, detaching from patients, perceived lack of control over EOHD criteria, and physical exhaustion from overextending to bridge care), 2) moral distress from propagating injustice (altered care based on nonmedical factors, focus on volume at the expense of quality, and need to game the system), 3) confusing and perverse financial incentives (wasting resources, confusing financial incentives, and concerns about sustainability), and 4) inspiration toward advocacy (deriving inspiration from patients and strengthened altruism).

Limitation:

Whether the findings apply to other settings is unknown, and social desirability response bias might have reduced reporting of negative perceptions and experiences.

Conclusion:

Clinicians in safety-net settings who provide EOHD to undocumented patients describe experiencing moral distress and being driven toward professional burnout. The burden of EOHD on clinicians should inform discussions of systemic approaches to support provision of adequate care based on medical need.

Primary Funding Source:

Robert Wood Johnson Foundation and Doris Duke Charitable Foundation.

https://ift.tt/2x0cem7

Annals Story Slam - Clerks, Codes, and Culture, or “We Weren't Even Supposed to Be Here!”

https://ift.tt/2NmBnuB

Association of Viral Suppression With Lower AIDS-Defining and Non–AIDS-Defining Cancer Incidence in HIV-Infected Veterans A Prospective Cohort Study

Background:

Viral suppression is a primary marker of HIV treatment success. Persons with HIV are at increased risk for AIDS-defining cancer (ADC) and several types of non–AIDS-defining cancer (NADC), some of which are caused by oncogenic viruses.

Objective:

To determine whether viral suppression is associated with decreased cancer risk.

Design:

Prospective cohort.

Setting:

Department of Veterans Affairs.

Participants:

HIV-positive veterans (n = 42 441) and demographically matched uninfected veterans (n = 104 712) from 1999 to 2015.

Measurements:

Standardized cancer incidence rates and Poisson regression rate ratios (RRs; HIV-positive vs. uninfected persons) by viral suppression status (unsuppressed: person-time with HIV RNA levels ≥500 copies/mL; early suppression: initial 2 years with HIV RNA levels <500 copies/mL; long-term suppression: person-time after early suppression with HIV RNA levels <500 copies/mL).

Results:

Cancer incidence for HIV-positive versus uninfected persons was highest for unsuppressed persons (RR, 2.35 [95% CI, 2.19 to 2.51]), lower among persons with early suppression (RR, 1.99 [CI, 1.87 to 2.12]), and lowest among persons with long-term suppression (RR, 1.52 [CI, 1.44 to 1.61]). This trend was strongest for ADC (unsuppressed: RR, 22.73 [CI, 19.01 to 27.19]; early suppression: RR, 9.48 [CI, 7.78 to 11.55]; long-term suppression: RR, 2.22 [CI, 1.69 to 2.93]), much weaker for NADC caused by viruses (unsuppressed: RR, 3.82 [CI, 3.24 to 4.49]; early suppression: RR, 3.42 [CI, 2.95 to 3.97]; long-term suppression: RR, 3.17 [CI, 2.78 to 3.62]), and absent for NADC not caused by viruses.

Limitation:

Lower viral suppression thresholds, duration of long-term suppression, and effects of CD4⁺ and CD8⁺ T-cell counts were not thoroughly evaluated.

Conclusion:

Antiretroviral therapy resulting in long-term viral suppression may contribute to cancer prevention, to a greater degree for ADC than for NADC. Patients with long-term viral suppression still had excess cancer risk.

Primary Funding Source:

National Cancer Institute and National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health.

https://ift.tt/2sOi3OY

Review: In uncontrolled, persistent asthma, adding LAMAs to inhaled corticosteroids reduce exacerbations

https://ift.tt/2mlyoHd

Associations Between American Board of Internal Medicine Maintenance of Certification Status and Performance on a Set of Healthcare Effectiveness Data and Information Set (HEDIS) Process Measures

Background:

The value of the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program has been questioned as a marker of physician quality.

Objective:

To assess whether physician MOC status is associated with performance on selected Healthcare Effectiveness Data and Information Set (HEDIS) process measures.

Design:

Annual comparisons of HEDIS process measures among physicians who did or did not maintain certification 20 years after initial certification.

Setting:

Fee-for-service Medicare.

Participants:

1260 general internists who were initially certified in 1991 and provided care for 85 931 Medicare patients between 2009 and 2012.

Measurements:

Annual percentage of a physician's Medicare patients meeting each of 5 HEDIS annual or biennial standards and a composite indicating meeting all 3 HEDIS diabetes standards.

Results:

Among the 1260 physicians, 786 maintained their certification from 1991 to 2012 and 474 did not. The mean annual percentage of HEDIS-eligible diabetic patients who completed semiannual hemoglobin A_1c testing was 58.4% among physicians who maintained certification and 54.4% among those who did not (regression-adjusted difference, 4.2 percentage points [95% CI, 2.0 to 6.5 percentage points]; P < 0.001). Diabetic patients of physicians who maintained certification more frequently met the annual standard for low-density lipoprotein (LDL) cholesterol measurement (83.1% vs. 80.5%; regression-adjusted difference, 2.3 percentage points [CI, 0.6 to 4.1 percentage points]; P = 0.008) and all 3 diabetic standards (46.0% vs. 41.6%; regression-adjusted difference, 3.1 percentage points [CI, 0.5 to 5.7 percentage points]; P = 0.019). The regression-adjusted difference in biennial eye examinations was statistically insignificant (P = 0.112). Measures for LDL cholesterol testing in patients with coronary heart disease and biennial mammography were also met more frequently among physicians who maintained certification (79.4% vs. 77.4% and 72.0% vs. 67.8%, respectively), with regression-adjusted differences of 1.7 percentage points (CI, 0.2 to 3.3 percentage points; P = 0.032) and 4.6 percentage points (CI, 2.9 to 6.3 percentage points; P < 0.001), respectively.

Limitation:

Potential confounding by unobserved patient, physician, and practice characteristics; inability to determine clinical significance of observed differences.

Conclusion:

Maintaining certification was positively associated with physician performance scores on a set of HEDIS process measures.

Primary Funding Source:

American Board of Internal Medicine.

https://ift.tt/2sPHtMd

Annals for Hospitalists - 17 July 2018

https://ift.tt/2NTVTDO

Marijuana Use, Respiratory Symptoms, and Pulmonary Function A Systematic Review and Meta-analysis

Background:

The health effects of smoking marijuana are not well-understood.

Purpose:

To examine the association between marijuana use and respiratory symptoms, pulmonary function, and obstructive lung disease among adolescents and adults.

Data Sources:

PubMed, Embase, PsycINFO, MEDLINE, and the Cochrane Library from 1 January 1973 to 30 April 2018.

Study Selection:

Observational and interventional studies published in English that reported pulmonary outcomes of adolescents and adults who used marijuana.

Data Extraction:

Four reviewers independently extracted study characteristics and assessed risk of bias. Three reviewers assessed strength of evidence. Studies of similar design with low or moderate risk of bias and sufficient data were pooled.

Data Synthesis:

Twenty-two studies were included. A pooled analysis of 2 prospective studies showed that marijuana use was associated with an increased risk for cough (risk ratio [RR], 2.04 [95% CI, 1.02 to 4.06]) and sputum production (RR, 3.84 [CI, 1.62 to 9.07]). Pooled analysis of cross-sectional studies (1 low and 3 moderate risk of bias) showed that marijuana use was associated with cough (RR, 4.37 [CI, 1.71 to 11.19]), sputum production (RR, 3.40 [CI, 1.99 to 5.79]), wheezing (RR, 2.83 [CI, 1.89 to 4.23]), and dyspnea (RR, 1.56 [CI, 1.33 to 1.83]). Data on pulmonary function and obstructive lung disease were insufficient.

Limitation:

Few studies were at low risk of bias, marijuana exposure was limited in the population studied, cohorts were young overall, assessment of marijuana exposure was not uniform, and study designs varied.

Conclusion:

Low-strength evidence suggests that smoking marijuana is associated with cough, sputum production, and wheezing. Evidence on the association between marijuana use and obstructive lung disease and pulmonary function is insufficient.

Primary Funding Source:

None. (PROSPERO: CRD42017059224)

https://ift.tt/2z5yTyq

Annals Story Slam - Seeing the Body, or Two Sparks

https://ift.tt/2NQZ2US

Clonal Hematopoiesis Confers Predisposition to Both Cardiovascular Disease and Cancer: A Newly Recognized Link Between Two Major Killers

The presence of a somatic mutation associated with hematologic cancer in the peripheral blood at a variant allele frequency of at least 2% in the absence of hematologic cancer defines clonal hematopoiesis of indeterminate potential (CHIP). This commentary discusses CHIP's potential in cardiovascular risk assessment and as a biomarker for response to interventions to reduce cardiovascular risk.

https://ift.tt/2xkkuNT

A Novel Strategy for Increasing Access to Treatment for Hepatitis C Virus Infection for Medicaid Beneficiaries

This commentary proposes a novel strategy for increasing access to treatment for hepatitis C virus infection for Medicaid beneficiaries. It posits a drug purchasing strategy that encourages competition among manufacturers that could save money for states and vastly expand treatment.

https://ift.tt/2L2OyAu

Review: More-intensive vs less-intensive LDL-cholesterol lowering reduces mortality

https://ift.tt/2mlaxrd

Starving the Hungry Tapeworm: How Businessmen May Reform Health Care Cost

News that the CEOs of Amazon, Berkshire Hathaway, and JPMorgan Chase are coming together to combat high health care costs has been met with anticipation and skepticism. This commentary speculates on how these business giants might apply a Six Sigma approach to achieve the cost containment that has so far eluded the U.S. health care system.

https://ift.tt/2IUsTsE

Annals Consult Guys – A Stumper: How Much Spent for How Much Prevention?

https://ift.tt/2NTu0fb

Dialysis Without Borders

The study by Cervantes and colleagues is the first to provide empirical evidence about the effects of EOHD on professionalism. The editorialist discusses the findings, draws parallels between providing standard dialysis to undocumented immigrants and providing universal health coverage to U.S. citizens, and proposes an approach to address the problem of EOHD.

https://ift.tt/2wZoYt0

Annals Story Slam - A Time to Die

https://ift.tt/2NXS4NM

Maintenance of Certification: Glass Not Entirely Empty?

Gray and colleagues report that Maintenance of Certification is correlated with small improvements in performance on several Healthcare Effectiveness Data and Information Set (HEDIS) metrics. The editorialist discusses these findings, the most disturbing of which is the overall low rates at which HEDIS standards were met and the minimally better performance among physicians who maintained certification.

https://ift.tt/2JDxyzF

Annals Story Slam - Getting to Know My People

https://ift.tt/2zLeq2f

RapidDeploy hires leading public safety GIS expert

RapidDeploy, a leader in cloud-based Computer-Aided Dispatch (CAD) technology, announced the hiring of Brooks Shannon as Vice President of Product Management. Shannon is a national subject matter expert in public safety Geographic Information Systems (GIS), and has been involved in numerous efforts to increase and enhance location accuracy for 911 systems. "Our CAD technology is already...

https://ift.tt/2JtK9Va

Suppression of PDHX by microRNA-27b deregulates cell metabolism and promotes growth in breast cancer

Abstract

Background

The disruption of normal gene regulation due to microRNA dysfunction is a common event in cancer pathogenesis. MicroRNA-27b is an example of an oncogenic miRNA, and it is frequently upregulated in breast cancer. MicroRNAs have been found to deregulate tumor metabolism, which typically manifests as heightened cellular glucose uptake in consort with increased flux through glycolysis, followed by the preferential conversion of glycolytic pyruvate into lactate (a phenomenon known as the Warburg Effect). Pyruvate Dehydrogenase, an enzyme complex linking glycolysis with downstream oxidative metabolism, represents a key location where regulation of metabolism occurs; PDHX is a key structural component of this complex and is essential for its function.

Methods

We sought to characterize the role of miR-27b in breast cancer by identifying novel transcripts under its control. We began by utilizing luciferase, RNA, and protein assays to establish PDHX as a novel target of miR-27b. We then tested whether miR-27b could alter metabolism using several metabolite assay kits and performed a seahorse analysis. We also examined how the altered metabolism might affect cell proliferation. Lastly, we confirmed the relevance of our findings in human breast tumor samples.

Results

Our data indicate that Pyruvate Dehydrogenase Protein X is a credible target of miR-27b in breast cancer. Mechanistically, by suppressing PDHX, miR-27b altered levels of pyruvate, lactate and citrate, as well as reducing mitochondrial oxidation and promoting extracellular acidification. These changes corresponded with an increased capacity for cell proliferation. In human breast tumor samples, PDHX expression was deficient, and low levels of PDHX were associated with reduced patient survival.

Conclusions

MicroRNA-27b targets PDHX, resulting in an altered metabolic configuration that is better suited to fuel biosynthetic processes and cell proliferation, thereby promoting breast cancer progression.

https://ift.tt/2Jy9f5c

Epidemiology of HBoV1 infection and relationship with meteorological conditions in hospitalized pediatric patients with acute respiratory illness: a 7-year study in a subtropical region

Human bocavirus 1 (HBoV1) is an important cause of acute respiratory illness (ARI), yet the epidemiology and effect of meteorological conditions on infection is not fully understood. To investigate the distrib...

https://ift.tt/2L22Pkz

Variability in distribution and use of tuberculosis diagnostic tests in Kenya: a cross-sectional survey

Globally, 40% of all tuberculosis (TB) cases, 65% paediatric cases and 75% multi-drug resistant TB (MDR-TB) cases are missed due to underreporting and/or under diagnosis. A recent Kenyan TB prevalence survey f...

https://ift.tt/2Juf6sl

Clinical management of respiratory syndrome in patients hospitalized for suspected Middle East respiratory syndrome coronavirus infection in the Paris area from 2013 to 2016

Patients with suspected Middle East respiratory syndrome coronavirus (MERS-CoV) infection should be hospitalized in isolation wards to avoid transmission. This suspicion can also lead to medical confusion and ...

https://ift.tt/2L1nCEY

Maternal and infant death after probable vertical transmission of chikungunya virus in Brazil – case report

Chikungunya virus infection in neonates is relatively rare and can lead to death.

https://ift.tt/2JuazpN

Preliminary results of official influenza and acute respiratory infection surveillance in two towns of Burkina Faso, 2013–2015

In 2010, influenza, influenza-like illness (ILI) and acute respiratory infection (ARI) surveillance was established by the government of Burkina Faso. We provide preliminary descriptive results from this surve...

https://ift.tt/2KXCWSO

Temporal association between antibiotic use and resistance in Klebsiella pneumoniae at a tertiary care hospital

β-Lactam/β-lactamase inhibitors (BLBLIs) were introduced into clinical practice as an alternative to carbapenems for treating multi-drug–resistant Klebsiella pneumoniae infections. However, little is known about ...

https://ift.tt/2uDu4Xy

Antibiotic use on paediatric inpatients in a teaching hospital in the Gambia, a retrospective study

Antibiotics are useful but increasing resistance is a major problem. Our objectives were to assess antibiotic use and microbiology testing in hospitalized children in the Gambia.

https://ift.tt/2uDk00Q

CNN models discriminating between pulmonary micro-nodules and non-nodules from CT images

Early and automatic detection of pulmonary nodules from CT lung screening is the prerequisite for precise management of lung cancer. However, a large number of false positives appear in order to increase the s...

https://ift.tt/2NiZFFG

Laboratory for Advanced Medicine commercializes non-invasive, artificial intelligence-based IvyGene Blood Test for early cancer detection

Company Expands Headquarters and National Workforce to Accommodate Rapid Growth IRVINE, Calif.—Laboratory for Advanced Medicine (LAM), a clinical-stage medical technology company developing innovative technologies for the early diagnosis and intervention of cancers, today announced the commercialization of its revolutionary, non-invasive and highly accurate IvyGene test. IvyGene is designed...

https://ift.tt/2mkFLi3

Annual First Responder Caring Award for 2018

ORANGEBURG, N.Y. – Dynarex, a leading medical products brand and provider of disposable medical supplies, is pleased to launch the 2nd Annual "First Responder Caring Award." The FRCA is to honor EMS/EMT first responders or first responder units who have gone above and beyond the call of duty. This year Dynarex will award one Grand Prize Winner with $2500 in Dynarex product and...

https://ift.tt/2NWhvzF

Key Factors Affecting the Performance of Sb2S3-sensitized Solar Cells During an Sb2S3 Deposition via SbCl3-thiourea Complex Solution-processing

This work provides a detailed experimental procedure for the deposition of Sb2S3 on a mesoporous TiO2 layer using a SbCl3-thiourea complex solution for applications in Sb2S3-sensitized solar cells. This article also determines key factors governing the deposition process.

https://ift.tt/2Lqxzrp

Nanosensors to Detect Protease Activity In Vivo for Noninvasive Diagnostics

Proteases are tightly regulated enzymes involved in fundamental biological processes, and dysregulated protease activity drives progression of complex diseases such as cancer. This method's goal is to create nanosensors that measure protease activity in vivo by producing a cleavage signal that is detectable from host urine and discriminates disease.

https://ift.tt/2LhukFY

EMTs help disabled pilot visit former airport

Two EMTs volunteered to help a former patient visit the airport where he was a pilot before suffering an aneurysm

https://ift.tt/2uuDEN6

PM2.5 Contributes to Burden of Diabetes Mellitus Globally

MONDAY, July 16, 2018 -- Particulate matter (PM) with a diameter of less than 2.5 micrograms per cubic meter of air (PM2.5) makes a substantial contribution to the burden of diabetes, according to a study published in the July issue of The Lancet...

https://ift.tt/2mll85q

Declines in Vision Tied to Age-Related Cognitive Decline

MONDAY, July 16, 2018 -- Older adults' worsening vision may drive declines in cognitive function, according to a study published online July 10 in JAMA Ophthalmology. D. Diane Zheng, from the University of Miami, and colleagues evaluated the...

https://ift.tt/2uBgTXh

Compassion Training May Up Resilience to Others' Suffering

MONDAY, July 16, 2018 -- Compassion meditation can increase the visual preference for suffering while attenuating neural responses in regions of the brain associated with valence and empathic distress, according to a study published recently in...

https://ift.tt/2mkuLkL

Quadrivalent HPV Vaccine Not Tied to Spontaneous Abortion

MONDAY, July 16, 2018 -- The quadrivalent human papillomavirus vaccine (4vHPV) is not associated with an increased risk of spontaneous abortion when inadvertently given before or during pregnancy, according to a study published in the July issue of...

https://ift.tt/2zLVFM4

Inappropriate Prescribing of Abx High in Urgent Care Centers

MONDAY, July 16, 2018 -- There is considerable variability in the proportion of visits at which antibiotics are prescribed among traditional medical and retail clinic settings, according to a research letter published online July 16 in JAMA Internal...

https://ift.tt/2mll6uk

Fake FDA Warning Letters Being Sent to Consumers

MONDAY, July 16, 2018 -- Criminals are sending fake U.S. Food and Drug Administration warning letters to people who tried to buy medicines online or over the phone. The agency notes that it does not typically send warning letters to individuals, and...

https://ift.tt/2uBgSmb

eCare Plan Set to Improve Doctor/Pharmacist Relationship

MONDAY, July 16, 2018 -- The Pharmacist eCare Plan is designed to improve communication between pharmacists and physicians by allowing documentation to be available via electronic health records (EHRs), according to an article published online in...

https://ift.tt/2mjyxuS